Chemoselective Silver-Catalyzed Nitrene Transfer: Tunable Syntheses of Azepines and Cyclic Carbamimidates.

Azepines and their saturated azepane counterparts are important moieties in bioactive molecules but are under-represented in current drug screening libraries. Herein, we report a mild and efficient azepine formation via silver-catalyzed dearomative nitrene transfer. A 2,2,2-trichloroethoxysulfonyl (Tces)-protected carbamimidate nitrene precursor, coupled with the appropriate ligand for silver, is essential for achieving the unexpected chemoselectivity between arene dearomatization and benzylic C(sp3)-H amination. Potential applications in the late-stage diversification of azepines to complex molecular scaffolds and diastereoselective hydrogenations to sp3-rich derivatives are also highlighted.

A Synthetic Strategy toward S-, N-, and O-Heterocyclooctynes Facilitates Bioconjugation Using Multifunctional Handles.

Over the past two decades, the introduction of bioorthogonal reactions has transformed the ways in which chemoselective labeling, isolation, imaging, and drug delivery are carried out in a complex biological milieu. A key feature of a good bioorthogonal probe is the ease with which it can be attached to a target compound through bioconjugation. This paper describes the expansion of the utility of a class of unique S-, N-, and O-containing heterocyclooctynes (SNO-OCTs), which show chemoselective reactivity with type I and type II dipoles and divergent reactivities in response to electronic tuning of the alkyne. Currently, bioconjugation of SNO-OCTs to a desired target is achieved through an inconvenient aryl or amide linker at the sulfamate nitrogen. Herein, a new synthetic approach toward general SNO-OCT scaffolds is demonstrated that enables the installation of functional handles at both propargylic carbons of the heterocycloalkyne. This capability increases the utility of SNO-OCTs as labeling reagents through the design of bifunctional bioorthogonal probes with expanded capabilities. NMR kinetics also revealed up to sixfold improvement in cycloaddition rates of new analogues compared to first-generation SNO-OCTs.

Progress toward the Total Synthesis of Nogalamycin Using a Benzyne Cycloaddition Strategy.

Nogalamycin (NOG) is a member of the anthracycline glycoside natural products; no total syntheses have yet been reported, and there is minimal understanding of how the aglycone substitution pattern and identities of the A- and D-ring sugars impact the anticancer activity and toxicity. This paper reports progress toward a modular approach to NOG that could enable systematic structure-activity relationship studies. Key steps include a regioselective benzyne cycloaddition and reductive ring-opening to assemble a versatile AB core for analogue synthesis.

Acylated and alkylated benzo(crown-ethers) form ion-dependent ion channels in biological membranes.

Synthetic ion channels based on benzo(crown-ether) compounds have been previously reported to function as ion-selective channels in planar lipid bilayers, with hydrogen bonding networks implicated in the formation of self-aggregated complexes. Herein, we report the synthesis and characterization of two new families of benzo(crown-ether) compounds, termed monoacylated and monoalkylated benzo(crown-ethers) (MABCE), both of which lack hydrogen bond donors. Depending on the length of alkyl chain substituent and the size of macrocycle, MABCE compounds inhibit bacterial growth and transport ions across biological membranes. Single-channel recordings show that the activity is higher in the presence of K+ as compared with Na+; however, under bionic conditions, open channels do not exhibit any preference between the two ions. These findings reveal that the ionic preference of benzo(crown-ether) compounds is either due to the regulation of assembly of ion-conducting supramolecular complexes or its membrane insertion by cations, as opposed to ion-selective transport through these scaffolds. Furthermore, our data show that the H-bonding network is not needed to form these assemblies in the membrane.

Origins of Catalyst-Controlled Selectivity in Ag-Catalyzed Regiodivergent C-H Amination.

Ag-catalyzed nitrene transfer (NT) converts C-H bonds into valuable C-N bonds. These reactions offer a promising strategy for catalyst-controlled regiodivergent functionalization of different types of reactive C-H bonds, as the regioselectivity is tunable by varying the steric and electronic environments around the Ag nitrene, as well as the identity of the nitrene precursors and the tether length. Therefore, a unified understanding of how these individual factors affect the regioselectivity is key to the rational design of highly selective and regiodivergent C-H amination reactions. Herein, we report a computational study of various Ag-catalyzed NT reactions that indicates a concerted H-atom transfer (HAT)/C-N bond formation mechanism. A detailed analysis was carried out on the effects of the C-H bond dissociation enthalpy (BDE), charge transfer, ligand-substrate steric repulsions, and transition state ring strain on the stability of the C-H insertion transition states with different Ag nitrene complexes. The ancillary ligands on the Ag and the nitrene precursor identity both affect transition state geometries to furnish differing sensitivities to the BDE, tether length, and electronic effects of the reactive C-H bonds. Based on our understanding of the dominant factors that control selectivity, we established a rational catalyst and precursor selection approach for regiodivergent amination of diverse C-H bonds. The computationally predicted regiodivergent amination of ß- and γ-C-H bonds of aliphatic alcohol derivatives was validated by experimental studies.

Pd-Catalyzed Heck-Type Reactions of Allenes for Stereoselective Syntheses of Substituted 1,3-Dienes.

A highly stereoselective Pd-catalyzed Heck-type reaction of allenes in which the stereochemistry of both olefins is set simultaneously was developed. The ligand CyJohnPhos was crucial to achieving stereoselectivity, while minimizing isomerization of the starting material through hydropalladation. The stereodetermining factors were proposed to be A1,3 strain between the catalyst and allene substituent, which influences the σ-π-σ equilibrium of the coupled allene intermediate, as well as eclipsing interactions of R groups in the ß-hydride elimination. Good functional group tolerance and stereoselectivities for formation of the Z,E isomer were demonstrated. The methodology was further expanded to include the regioselective formation of 2,4-dienoates and 2,4-dienamides with a variety of substitution patterns, albeit in reduced stereoselectivities favoring the E,E isomer. A plausible mechanism is proposed to account for the observed selectivities and substituent effects.

Re-Evaluation of Product Outcomes in the Rh-Catalyzed Ring Expansion of Aziridines with N-Sulfonyl-1,2,3-Triazoles.

N-heterocycles are prevalent in pharmaceuticals and natural products, but traditional methods often do not introduce significant stereochemical complexity into the ring. We previously reported a Rh-catalyzed ring expansion of aziridines and N-sulfonyl-1,2,3-triazoles to furnish dehydropiperazines with excellent diastereocontrol. However, later studies employing ketone-containing carbene precursors showed that [3,9]-bicyclic aziridine formation competes with production of the desired heterocyclic scaffolds. In light of these surprising results, our initial findings were re-examined both experimentally and computationally to reveal how noncovalent interactions and restricted bond rotation in the aziridinium ylide intermediate promote this unexpected reaction pathway.

Recent Developments and Strategies for Mutually Orthogonal Bioorthogonal Reactions.

Over the past decade, several different metal-free bioorthogonal reactions have been developed to enable simultaneous double-click labeling with minimal-to-no competing cross-reactivities; such transformations are termed 'mutually orthogonal'. More recently, several examples of successful triple ligation strategies have also been described. In this minireview, we discuss selected aspects of the development of orthogonal bioorthogonal reactions over the past decade, including general strategies to drive future innovations to achieve simultaneous, mutually orthogonal click reactions in one pot.

Allene Trifunctionalization via Amidyl Radical Cyclization and TEMPO Trapping.

Radical-mediated trifunctionalizations of allenes are virtually unknown, in contrast to well-studied radical difunctionalizations of alkenes and alkynes. In this article, we describe a light-promoted reaction that transforms all three allene carbons to new carbon-heteroatom bonds in one pot with no expensive transition-metal catalyst. Formation of an electron donor-acceptor complex between an electron-deficient aryl and K2CO3, followed by photochemical generation of an amidyl radical and cyclization, yields a vinyl radical that can be trapped by TEMPO to ultimately furnish the product. Insights into the impact of the allene substitution pattern, radical source, and donor are presented, along with studies to unravel the mechanism of this unusual transformation.

Mechanistic Aspects and Synthetic Applications of Radical Additions to Allenes.

More than 50 years have passed since Haszeldine reported the first addition of a trifluoromethyl radical to an allene; in the intervening years, both the chemistry of allenes and the reactivity of single-electron species have become topics of intense interest. In this Review, we provide an overview of the fundamentals of radical additions to allenes and highlight the emergence of theoretical and experimental evidence that reveals unique reactivity patterns for radical additions to allenes as compared with other unsaturated compounds. Factors capable of exerting control over the chemo-, regio-, and stereoselectivities of the attack of carbon- and heteroatom-based radicals at each of the three potential reactive sites in an allene substrate are described. These include reaction conditions, the nature of the attacking radical, the substitution pattern of the allene, and the length of the linker between the radical center and the proximal allene carbon in the substrate. Cycloaddition reactions between allenes and partners containing π-bonds, which are likely to proceed through radical pathways, are presented to highlight their ability to rapidly access complex polycyclic scaffolds. Finally, the synthetic utility of the products arising from these chemistries is described, including their applications to the construction of complex molecules.

Strategies for the Syntheses of Pactamycin and Jogyamycin.

Pactamycin and jogyamycin are aminocyclopentitol natural products, where each core carbon bears a stereodefined alcohol or amine moiety. Their structural complexity, coupled with the diversity of functional groups coexisting in a condensed space, make them fascinating synthetic targets in their own right. Pactamycin and its derivatives bind to the 30S ribosomal subunit and display activity against parasites responsible for drug-resistant malaria and African sleeping sickness; however, efforts to develop their therapeutic potential have been hampered by their cellular toxicity. Interestingly, bioengineered analogues display differences in selectivity and toxicity towards mammalian cells, spurring efforts to develop flexible strategies to thoroughly probe structure-activity relationships (SAR), particularly in analogues lacking the C7 hydroxyl group of pactamycin. This review compares and contrasts approaches towards pactamycin and jogyamycin, including two successful total syntheses of the former. The implications of each route for preparing analogues to inform SAR and lead to compounds with increased selectivity for binding malarial over human ribosomes are briefly discussed.

Biomimetic 2-Imino-Nazarov Cyclizations via Eneallene Aziridination.

Amidoallyl cations are appealing three-carbon synthons for the preparation of complex amine-containing carbocycles; however, methods to generate and utilize these reactive species are limited and underexplored compared to those for oxallyl cations. Here we disclose a bioinspired strain-driven ring opening of bicyclic methyleneaziridines to 2-amidopentadienyl cation intermediates that readily engage in Nazarov cyclizations. Advantages of this strategy include ease of generation and improved reactivity compared to 3-pentadienyl cations, control over the ultimate position of the alkene, the potential for high dr between vicinal stereocenters, and the ability to further elaborate the products to fully substituted aminocyclopentanes. Experimental and computational studies support a dual role for the Rh2Ln complex as both a nitrene transfer catalyst and a Lewis acid promoter, insight that provides a framework for the future development of asymmetric 2-imino-Nazarov cyclizations.

Silver-Catalyzed Enantioselective Propargylic C-H Bond Amination through Rational Ligand Design.

Asymmetric C-H amination via nitrene transfer is a powerful tool to prepare enantioenriched amine precursors from abundant C-H bonds. Herein, we report a regio- and enantioselective synthesis of γ-alkynyl γ-aminoalcohols via a silver-catalyzed propargylic C-H amination. The protocol was enabled by a new bis(oxazoline) (BOX) ligand designed via a rapid structure-activity relationship (SAR) analysis. The method utilizes accessible carbamate esters bearing γ-propargylic C-H bonds and furnishes versatile products in good yields and excellent enantioselectivity (90-99% ee). The putative Ag-nitrene is proposed to undergo enantiodetermining hydrogen-atom transfer (HAT) during the C-H amination event. Density functional theory calculations shed insight into the origin of enantioselectivity in the HAT step.

Triple, Mutually Orthogonal Bioorthogonal Pairs through the Design of Electronically Activated Sulfamate-Containing Cycloalkynes.

Interest in mutually exclusive pairs of bioorthogonal labeling reagents continues to drive the design of new compounds that are capable of fast and predictable reactions. The ability to easily modify S-, N-, and O-containing cyclooctynes (SNO-OCTs) enables electronic tuning of various SNO-OCTs to influence their cycloaddition rates with Type I-III dipoles. As opposed to optimizations based on just one specific dipole class, the electrophilicity of the alkynes in SNO-OCTs can be manipulated to achieve divergent reactivities and furnish mutually orthogonal dual ligation systems. Significant reaction rate enhancements of a difluorinated SNO-OCT derivative, as compared to the parent scaffold, were noted, with the second-order rate constant in cycloadditions with diazoacetamides exceeding 5.13 M-1 s-1. Computational and experimental studies were employed to inform the design of triple ligation systems that encompass three orthogonal reactivities. Finally, polar SNO-OCTs are rapidly internalized by mammalian cells and remain functional in the cytosol for live-cell labeling, highlighting their potential for diverse in vitro and in vivo applications.

Regioselective Intramolecular Allene Amidation Enabled by an EDA Complex*.

The addition of radicals to unsaturated precursors is a powerful tool for the synthesis of both carbo- and heterocyclic organic building blocks. The recent advent of mild ways to generate N-centered radicals has reignited interest in exploiting highly regio-, chemo-, and stereoselective transformations that employ these reactive intermediates. While the additions of aminyl, iminyl, and amidyl radicals to alkenes and alkynes have been well-studied, analogous additions to allenes are scarce. Allenes offer several attractive features, including potential for selective amidation at three distinct sites via judicious choice of precursor or radical source, the opportunity for axial-to-point chirality transfer, and productive trapping of vinyl or allyl radical intermediates to diversify functionality in the products. In this article, we report a regioselective addition of amidyl radicals to allenes to furnish an array of valuable N-heterocycle scaffolds.

Stereocontrolled Synthesis of the Aminocyclopentitol Core of Jogyamycin via an Ichikawa Rearrangement Reaction.

Jogyamycin is a member of the aminocyclopentitol class of natural products that exhibits significant antiprotozoal activities against diseases that include African sleeping sickness and malaria. Herein, we report a route to the core of this natural product via an underutilized Ichikawa rearrangement as a key step. This route efficiently forms the cyclopentane ring from simple and easily accessible starting materials and rapidly installs the C1/C4/C5 polar functional groups. In addition, this strategy shows excellent potential for the preparation of analogues of jogyamycin to study how structural changes impact the selectivity in binding to the ribosome.

Tunable, Chemo- and Site-Selective Nitrene Transfer Reactions through the Rational Design of Silver(I) Catalysts.

Carbon-nitrogen (C-N) bonds are ubiquitous in pharmaceuticals, agrochemicals, diverse bioactive natural products, and ligands for transition metal catalysts. An effective strategy for introducing a new C-N bond into a molecule is through transition metal-catalyzed nitrene transfer chemistry. In these reactions, a metal-supported nitrene can either add across a C═C bond to form an aziridine or insert into a C-H bond to furnish the corresponding amine. Typical catalysts for nitrene transfer include Rh2Ln and Ru2Ln complexes supported by bridging carboxylate and related ligands, as well as complexes based on Cu, Co, Ir, Fe, and Mn supported by porphyrins and related ligands. A limitation of metal-catalyzed nitrene transfer is the ability to predictably select which specific site will undergo amination in the presence of multiple reactive groups; thus, many reactions rely primarily on substrate control. Achieving true catalyst-control over nitrene transfer would open up exciting possibilities for flexible installation of new C-N bonds into hydrocarbons, natural product-inspired scaffolds, existing pharmaceuticals or biorenewable building blocks. Silver-catalyzed nitrene transfer enables flexible control over the position at which a new C-N bond is introduced. Ag(I) supported by simple N-donor ligands accommodates a diverse range of coordination geometries, from linear to tetrahedral to seesaw, enabling the electronic and steric parameters of the catalyst to be tuned independently. In addition, the ligand, Ag salt counteranion, Ag/ligand ratio and the solvent all influence the fluxional and dynamic behavior of Ag(I) complexes in solution. Understanding the interplay of these parameters to manipulate the behavior of Ag-nitrenes in a predictable manner is a key design feature of our work. In this Account, we describe successful applications of a variety of design principles to tunable, Ag-catalyzed aminations, including (1) changing Ag/ligand ratios to influence chemoselectivity, (2) manipulating the steric environment of the catalyst to achieve site-selective C-H bond amination, (3) promoting noncovalent interactions between Ag/substrate or substrate/ligand to direct C-H functionalization, and (4) dictating the substrate's trajectory of approach to the Ag-nitrene. Our catalysts distinguish between the aminations of various types of C-H bonds, including tertiary C(sp3)-H, benzylic, allylic, and propargylic C-H bonds. Efforts in asymmetric nitrene transfer reactions catalyzed by Ag(I) complexes are also described.

α-Tetrasubstituted Aldehydes through Electronic and Strain-Controlled Branch-Selective Stereoselective Hydroformylation.

Hydroformylation utilizes dihydrogen, carbon monoxide, and a catalyst to transform alkenes into aldehydes. This work applies chiral bisdiazaphospholane (BDP)- and bisphospholanoethane-ligated rhodium complexes to the hydroformylation of a variety of alkenes to produce chiral tetrasubstituted aldehydes. 1,1'-Disubstituted acrylates bearing electron-withdrawing substituents undergo hydroformylation under mild conditions (1 mol % of catalyst/BDP ligand, 150 psig gas, 60 °C) with high conversions and yields of tetrasubstituted aldehydes (e.g., 13:1 regioselectivity, 85% ee, and <1% hydrogenation for 1-fluoromethyl acrylate). The scope also encompasses both acyclic 1,1'-disubstituted and trisubstituted, electron-poor alkenes as well as di- and trisubstituted alkenes composed of small rings with exocyclic and endocyclic unsaturation. For example, 1-methylene-ß-lactam furnished the tetrasubstituted aldehyde with 98% selectivity and up to 83% ee. Notably, chiral trisubstituted bicyclic methyleneaziridines are transformed with >99% regioselectivity and >19:1 diastereoselectivity to tetrasubstituted aldehydes at rates >50 catalyst turnovers/hour. NMR studies of the noncatalytic reaction of HRh(BDP)(CO)2 with methyl 1-fluoroacrylate enable interception of tertiary alkylrhodium intermediates, demonstrating migratory insertion to acyl species is slower than formation of secondary and primary alkylrhodium intermediates. Overall, these investigations reveal how the interplay of sterics, electronics, and ring strain are harnessed to provide access to valuable α-tetrasubstituted aldehyde synthetic building blocks by promoting branched-selective hydroformylation.

Method for Small-Scale Production of Deuterochloroform.

Deuterochloroform (CDCl3) is a common deuterated solvent for nuclear magnetic resonance (NMR) analyses. The synthesis of significant amounts of CDCl3 for both research use and large undergraduate organic laboratories in a safe and inexpensive manner is appealing. Herein, we describe a convenient laboratory scale preparation of CDCl3 that employs a reduction and decarboxylation of hexachloro-2-propanone (HCP) catalyzed by various pyridines. A PVP catalyst gives cleaner reaction and greater catalyst stability through multiple rounds of recycling, justifying its higher cost compared to pyridine.

Investigation of transition metal-catalyzed nitrene transfer reactions in water.

Transition metal-catalyzed nitrene transfer is a powerful method for incorporating new CN bonds into relatively unfunctionalized scaffolds. In this communication, we report the first examples of site- and chemoselective CH bond amination reactions in aqueous media. The unexpected ability to employ water as the solvent in these reactions is advantageous in that it eliminates toxic solvent use and enables reactions to be run at increased concentrations with lower oxidant loadings. Using water as the reaction medium has potential to expand the scope of nitrene transfer to encompass a variety of biomolecules and highly polar substrates, as well as enable pH control over the site-selectivity of CH bond amination.